Combination comprising a glucocorticoid and edo-s101

ABSTRACT

The present invention is directed to a combination comprising a glucocorticoid and a compound of formula I or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     to a pharmaceutical composition and to a kit both comprising said combination, to the combination, composition or kit for use in the treatment of cancer, and to a method of treatment of cancer in a patient in need thereof comprising administering to said patient an effective amount of said combination, composition or kit.

TECHNICAL FIELD

The present invention relates to combinations and compositions that areof use in the treatment of cancer, for example in the treatment ofbreast cancer or of hematologic cancers such as multiple myeloma,lymphoma or leukemia.

BACKGROUND TO THE INVENTION

Cancer is one of the most life threatening diseases. Cancer is acondition in which cells in a part of the body experience out-of-controlgrowth. According to latest data from American Cancer Society, it isestimated there will be 1.67 million new cases of cancer in USA in 2014.Cancer is the second leading cause of death in the United States (secondonly to heart disease) and will claim more than 585,000 lives in 2014.In fact, it is estimated that 50% of all men and 33% of all women livingin the United States will develop some type of cancer in their lifetime.Therefore cancer constitutes a major public health burden and representsa significant cost in the United States. These figures are reflectedelsewhere across most countries globally, although the types of cancerand relative proportions of the population developing the cancers varydepending upon many different factors such including genetics and diet.

For decades surgery, chemotherapy, and radiation were the establishedtreatments for various cancers. Patients usually receive a combinationof these treatments depending upon the type and extent of their disease.But chemotherapy is the most important option for cancer patients whensurgery treatment is impossible. While surgery is sometimes effective inremoving tumors located at certain sites, for example, in the breast,colon, and skin, it cannot be used in the treatment of tumors located inother areas, such as the backbone, nor in the treatment of disseminatedhematologic cancers include cancers of the blood and blood-formingtissues (such as the bone marrow). They include multiple myeloma,lymphoma and leukemia. Radiation therapy involves the exposure of livingtissue to ionizing radiation causing death or damage to the exposedcells. Side effects from radiation therapy may be acute and temporary,while others may be irreversible. Chemotherapy involves the disruptionof cell replication or cell metabolism. It is used most often in thetreatment of breast, lung, and testicular cancer. One of the main causesof failure in this treatment of cancer is the development of drugresistance by the cancer cells, a serious problem that may lead torecurrence of disease or even death. Thus, more effective cancertreatments are needed.

Multiple myeloma is a significant and growing problem. It is a cancerarising from plasma cells. Normal plasma cells produce immunoglobulinsto fight infection. In myeloma, the plasma cells become abnormal,multiply uncontrollably and release only one type of antibody—known asparaprotein—which has no useful function. It tends to accumulate in thebone marrow and circulate in the blood and can be detected in the urineas well. It affects multiple sites in the body (hence ‘multiple’myeloma) where bone marrow is normally active in adults. The main formsof multiple myeloma (or myeloma as it is also referred to) are activemyeloma, plasmacytoma, light chain myeloma and non-secretory myeloma.The number of new cases of myeloma in the US in 2011 was 6.1 per 100,000men and women per year and the percentage survival rate beyond fiveyears was 45%. It is estimated that the number of new cases in the US in2014 will be over 24,000 (1.4% of all cancer cases), while the number ofdeaths in 2014 will be just over 11,000 (1.9% of all cancer cases).

In WO-A-2010/085377, the compound of formula I was shown to haveexcellent in vitro activity against multiple myeloma cell lines, withactivities in the range of □35-100 greater than the activity shown bybendamustin.

Leukemia is a type of cancer of the blood or bone marrow characterizedby an abnormal increase of immature white blood cells called “blasts”.Instead of producing normal, functioning white blood cells to fightinfection the body produces large numbers of these non-functionalblasts. Leukemia is a broad term covering a spectrum of diseases. Inturn, it is part of the even broader group of diseases affecting theblood, bone marrow and lymphoid system, which are all known ashematological neoplasms. The most common forms are acute lymphoblasticleukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloidleukemia (AML) and chronic myeloid leukemia (CML), with less commonforms including hairy cell leukemia (HCL), T-cell prolymphocyticleukemia (T-PLL), large granular lymphocytic leukemia and T-cell acutelymphoblastic leukemia. It is estimated that the number of new cases inthe United States in 2014 will be over 52,000 (3.1% of all new cancersin the US) with over 24,000 deaths (4.1% of all cancer deaths in theUS). The percentage survival rate over five years is currently 57.2%, afigure significantly lower than for many other cancers, with thesurvival rate over five years for acute myeloid leukemia beingparticularly low at only 20%.

Lymphoma is a cancer of the lymphatic system. There are two main typesof lymphoma, namely Hodgkin lymphoma and non Hodgkin lymphoma.

Non Hodgkin lymphoma is the more common form of lymphoma. The lymphaticsystem runs throughout the body, and it is therefore possible to findnon Hodgkin lymphoma in almost all parts of the body. In patients withnon Hodgkin lymphoma, some of their white blood cells (lymphocytes)divide abnormally. They do not have any resting time like normal cellsand they start to divide continuously, so too many are produced. They donot naturally die off as they usually do. These cells start to dividebefore they are fully mature and therefore cannot fight infection asnormal white blood cells do. All the abnormal lymphocytes start tocollect in the lymph nodes or other places such as the bone marrow orspleen. They can then grow into tumours and begin to cause problemswithin the lymphatic system or the organ in which they are growing. Forexample, if a lymphoma starts in the thyroid gland it can affect thenormal production of thyroid hormones. There are many different types ofnon Hodgkin lymphoma. They can be classified in several different ways.One way is by the type of cell affected. In non Hodgkin lymphoma twotypes of lymphocyte can be affected—B cells and T cells. This isclassified as B cell lymphoma or a T cell lymphoma. Most people with nonHodgkin lymphoma have B cell lymphomas. T cell lymphomas are more commonin teenagers and young adults.

The cells of Hodgkin lymphoma have a particular appearance under themicroscope. These cells are called Reed Sternberg cells. Non Hodgkinlymphomas do not have Reed Sternberg cells. It is important for doctorsto be able to tell the difference between Hodgkin lymphoma and nonHodgkin lymphoma cells as they are two different diseases. In Hodgkinlymphoma, it is cells in the lymph nodes that have become cancerous.

The % survival rate over 5 years in 2009 for patients with non Hodgkinlymphoma was 63%, while the survival rate for those with Hodgkinlymphoma over the same period was 83%.

Breast cancer is a cancer that forms in tissues of the breast. The mostcommon type of breast cancer is ductal carcinoma, which begins in thelining of the milk ducts (thin tubes that carry milk from the lobules ofthe breast to the nipple). Another type of breast cancer is lobularcarcinoma, which begins in the lobules (milk glands) of the breast.Breast cancers can be classified into sub-groups as claudin-low tumors,basal-like tumors, human epidermal growth factor receptor 2 (HER2)positive tumors, luminal A tumors and luminal B tumors. Invasive breastcancer is breast cancer that has spread from where it began in thebreast ducts or lobules to surrounding normal tissue. Breast canceroccurs in both men and women, although male breast cancer is rare. In2014, it is estimated that there will be nearly 233,00 new cases inwomen and 2,400 in men, with 40,00 female deaths and just over 400 maledeaths.

Approximately 15 out of every 100 women with breast cancer havetriple-negative breast cancer, i.e. are estrogen negative, areprogesterone negative and are HER2 negative. Recurrent triple-negativebreast cancer is a condition of high unmet medical need, due to itsaggressive biology, fast development of drug resistance and lack ofmolecular targets. Until now, chemotherapy remains the standard of carefor advanced triple-negative breast cancer with a poor median overallsurvival.

In WO-A-2010/085377, the compound of formula I below is disclosed. It isa first-in-class dual-functional alkylating-HDACi fusion molecule whichpotently inhibits the HDAC pathway.

Biological assays showed that the compound of formula I potentlyinhibits HDAC enzyme (HDAC1 IC₅₀ of 9 nM) and it has been shown to haveexcellent in vitro activity against multiple myeloma cell lines.

There is a need for more effective cancer treatments, including thetreatment of breast cancer and of hematologic cancers such as multiplemyeloma, lymphoma or leukemia. Currently, these conditions affect manypeople and the medium to long-term prognosis is not good for many ofthese conditions.

SUMMARY OF THE INVENTION

In a first aspect of the present invention, there is provided acombination comprising a glucocorticoid and a compound of formula I or apharmaceutically salt thereof:

The present inventors have found that combinations of a compound offormula I or a pharmaceutically acceptable salt thereof and aglucocorticoid such as dexamethasone or prednisone are particularlyeffective in the treatment of cancers including hematologic cancers suchas multiple myeloma, lymphoma and leukemia, and breast cancer. They arehighly promising in efforts to address the problem of finding moreeffective treatments for cancer. The combinations may optionally furthercomprise a proteasome inhibitor such as carfilzomib or bortezomib. Thesefurther combinations are also particularly effective in the treatment ofcancer.

In a second aspect of the present invention, there is provided apharmaceutical composition comprising a pharmaceutically acceptablediluent or carrier and a combination according to the first aspect ofthe invention.

In a third aspect of the present invention, there is provided a kitcomprising a combination according to the first aspect of the presentinvention and, optionally, instructions for treating a patient.

In a fourth aspect of the present invention, there is provided acombination, composition or kit according to the first, second or thirdaspect of the present invention for use in the treatment of cancer.

In a fifth aspect of the present invention, there is provided a methodof treating cancer in a patient in need thereof comprising administeringto said patient a combination, composition or kit according to thefirst, second or third aspect of the present invention.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the % surviving in vitro MM1S multiple myeloma cellsas a % of control versus concentration for different tested compoundsafter 48 hours incubation, for single compounds and as combinations(double and triple);

FIG. 2 is a plot of the % surviving in vitro MM1S multiple myeloma cellsas a % of control versus concentration for different tested compoundsafter 72 hours incubation, for single compounds and as combinations(double and triple); and

FIG. 3 is a plot of tumour growth (mm³) against the number of days ofstudy for different tested compounds for CB17-SCID mice subcutaneouslyinoculated into the right flank with 3×10⁶ MM1S cells, for singlecompounds and as combinations.

DETAILED DESCRIPTION OF THE INVENTION

In the present application, a number of general terms and phrases areused, which should be interpreted as follows.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids, or withorganic acids. Pharmaceutically acceptable salts also include baseaddition salts which may be formed when acidic protons present arecapable of reacting with inorganic or organic bases. Generally, suchsalts are, for example, prepared by reacting the free acid or base formsof these compounds with a stoichiometric amount of the appropriate baseor acid in water or in an organic solvent or in a mixture of the two.Generally, non-aqueous media like ether, ethyl acetate, ethanol,isopropanol or acetonitrile are preferred. Examples of the acid additionsalts include mineral acid addition salts such as, for example,hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, sulfamate,nitrate, phosphate, and organic acid addition salts such as, forexample, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate,succinate, tartrate, salicylate, tosylate, lactate,naphthalenesulphonae, malate, mandelate, methanesulfonate andp-toluenesulfonate. Examples of the alkali addition salts includeinorganic salts such as, for example, sodium, potassium, calcium andammonium salts, and organic alkali salts such as, for example,ethylenediamine, ethanolamine, N,N-dialkylenethanolamine,triethanolamine and basic aminoacids salts.

It has surprisingly been discovered that combinations of a compound offormula I or a pharmaceutically acceptable salt thereof and aglucocorticoid such as dexamethasone are particularly effective in thetreatment of cancers including hematologic cancers such as multiplemyeloma, leukemia and lymphoma, and breast cancer such that they arehighly promising in efforts to address the problem of finding moreeffective treatments for cancer. The combinations may optionally furthercomprise a proteasome inhibitor such as carfilzomib or bortezomib. Thesefurther combinations are also particularly effective in the treatment ofcancer.

In the combination of the present invention, the pharmaceuticallyacceptable salt of the compound of formula I may preferably be thehydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, sulfamate,nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate,glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate,tartrate, tosylate, salicylate, lactate, naphthalenesulfonate oracetate, and more preferably the acetate.

In the combination of the present invention, the glucocorticoid may forexample be selected from the group consisting of dexamethasone,fluocinolone acetonide and prednisone, of which dexamethasone ispreferred.

The combination of the present invention may further comprise aproteasome inhibitor. Suitable examples of proteasome inhibitors for usein the combination of the present invention include bortezomib,carfilzomib, marizomib, delanzomib (CEP-18770), oprozomib (ONX 0912),ixazomib (MLN-9708) and LU-102. Of these, bortezomib, carfilzomib andLU-102 are preferred.

The structures of these proteasome inhibitors are as follows:

In one further preferred combination of the present invention comprisinga compound of formula I or a pharmaceutically acceptable salt thereof, aglucocorticoid and optionally a proteasome inhibitor, said combinationmay further comprise one or more additional pharmaceutically activeagents. Particularly suitable pharmaceutically active agents areanti-tumor agents having a different mode of action to the compound offormula I or a pharmaceutically acceptable salt thereof, theglucocorticoid and the proteasome inhibitor, e.g. alkylating agents suchas nitrosureas, ethylenimines, alkylsulfonates, hydrazines andtriazines, and platinum based agents; plant alkaloids, taxanes, vincaalkaloids; anti-tumor antibiotics such as chromomycins, anthracyclines,and miscellaneous antibiotics such as Mitomycin and Bleomycin;anti-metabolites such as folic acid antagonists, pyrimidine antagonists,purine antagonists and adenosine deaminase inhibitors; topoisomeraseinhibitors such as topoisomerase I inhibitors, topoisomerase IIinhibitors, miscellaneous anti-neoplastics such as ribonucleotidereductase inhibitors, adrenocortical steroid inhibitor, anti-microtubuleagents, and retinoids; protein kinases; heat shock proteins, poly-ADP(adenosine diphosphate)-ribose polymerase (PARP), hypoxia-induciblefactors (HIF), proteasome, Wnt/Hedgehog/Notch signaling proteins,TNF-alpha, matrix metalloproteinase, farnesyl transferase, apoptosispathway, histone deacetylases (HDAC), histone acetyltransferases (HAT),and methyltransferase; hormonal therapies, vascular disrupting agent,gene therapy, RNAi cancer therapy, chemoprotective agents, antibodyconjugate, cancer immunotherapy such as Interleukin-2, cancer vaccinesor monoclonal antibodies; and preferably DNA damaging agents,anti-metabolites, topoisomerase inhibitors, anti-microtubule agents,EGFR inhibitors, HER2 inhibitors, VEGFR2 inhibitors, BRAF inhibitors,Bcr-Abl inhibitors, PDGFR inhibitors, ALK inhibitors, PLK inhibitors,MET inhibitors, epigenetic agents, HSP90 inhibitors, PARP inhibitors,CHK inhibitors, aromatase inhibitor, estrogen receptor antagonist, andantibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, etc.

In one embodiment of the combination of the present invention, thecompound of formula I or a pharmaceutically acceptable salt thereof, theglucocorticoid and, if present, the proteasome inhibitor are adapted foradministration concurrently, sequentially or separately. Preferably, thecompound of formula I or a pharmaceutically acceptable salt thereof, theglucocorticoid and, if present, the proteasome inhibitor are adapted foradministration concurrently.

In one embodiment of the combination of the present invention, theglucocorticoid is dexamethasone and the compound of formula I or apharmaceutically acceptable salt thereof is

or the acetate salt thereof. This combination may optionally furthercomprise a proteasome inhibitor selected from bortezomib, carfilzomiband LU-102.

In one embodiment of the combination of the present invention, the molarratio of glucocorticoid to compound of formula I or a pharmaceuticallyacceptable salt thereof in said combination is from 1:500 to 500:1.Preferably, the molar ratio of glucocorticoid to compound of formula Ior a pharmaceutically acceptable salt thereof in said combination isfrom 1:500 to 1:100, more preferably 1:300 to 1:100, and most preferablyfrom 1:250 to 1:150, e.g. 1:150, 1:200, 1:250 or 1:300.

One particularly preferred embodiment of the combination of the presentinvention comprises the compound of formula I or the acetate saltthereof and dexamethasone, wherein the molar ratio of the dexamethasoneto the compound of formula I or the acetate salt thereof in saidcombination is from 1:250 to 1:150, e.g. 1:150, 1:200 or 1:250.

It has been surprisingly found that many of the combinations comprisinga glucocorticoid and a compound of formula I or a pharmaceuticallyacceptable salt thereof are synergistic combinations. In other words,the potency of the combinations has been measured with the Calcusynsoftware (biosoft, Ferguson, Mo., USA), which is based on the Chou Talaymethod (Chou et al., Adv. Enzyme Regul., 22, 27-55 (1984)), thatcalculates a combination index (CI) with the following interpretation:

CI 1>1: antagonist effect, CI=1: additive effect and CI<1 synergisticeffect.

For many of the dual combinations of the present invention comprising aglucocorticoid and a compound of formula I or a pharmaceuticallyacceptable salt, CI has been found to be less than 1, indicatingsynergy.

Another embodiment of the combination of the present invention furthercomprises a proteasome inhibitor wherein the molar ratio of proteasomeinhibitor to the compound of formula I or a pharmaceutically acceptablesalt thereof to the glucocorticoid in said combination is from 1:1000:20to 1000:1:20. Preferably, the molar ratio of proteasome inhibitor to thecompound of formula I or a pharmaceutically acceptable salt thereof tothe glucocorticoid in said combination is from 1:1000:10 to 1:100:2.More preferably, the molar ratio of proteasome inhibitor to the compoundof formula I or a pharmaceutically acceptable salt thereof to theglucocorticoid used in said combination is from 1:1000:5 to 1:200:2, andmost preferably 1:700:4 to 1:400:3, e.g. 1:1000:5, 1:900:5, 1:800:4,1:700:4, 1:600:4, 1:500:3 or 1:400:3.

One particularly preferred combination of the present inventioncomprises a proteasome inhibitor selected from bortezomib andcarfilzomib, a compound of formula I or the acetate salt thereof anddexamethasone, wherein the molar ratio of the proteasome inhibitorselected from bortezomib and carfilzomib to the compound of formula I orthe acetate salt thereof to dexamethasone in said combination is from1:700:4 to 1:400:3, e.g. 1:700:4, 1:700:3, 1:600:4, 1:600:3, 1:500:3 or1:400:3. Another particularly preferred combination of the first aspectof the present invention comprises a proteasome inhibitor selected fromLU-102, the compound of formula I or the acetate salt thereof anddexamethasone, wherein the molar ratio of LU-102 to the compound offormula I or the acetate salt thereof to dexamethasone in saidcombination is from 1:3:4 to 1:0.5:3, e.g. 1:3:4, 1:3:3, 1:2:4, 1:2:3,1:1:4, 1:1:3 or 1:0.5:3.

It has also been surprisingly discovered that many of the triplecombinations of the present invention comprising a proteasome inhibitor,a compound of formula I or a pharmaceutically acceptable salt thereofand a glucocorticoid are also synergistic combinations, i.e. thecombination index CI has been found to be less than 1.

The pharmaceutical composition according to the second aspect of thepresent invention comprises a pharmaceutically acceptable diluent orcarrier and a combination according to the first aspect of the presentinvention. Preferred compositions of the second invention include thosecomprising the preferred combinations of the present invention asdescribed and exemplified above. The pharmaceutically acceptable diluentor carrier of the pharmaceutical composition according to the secondaspect of the present can be any suitable dispersant, excipient,adjuvant, or other material which acts as a carrier for the activeagents of the combination of the present invention and which does notinterfere with the active agents present in said combination. Examplesof typical pharmaceutically acceptable carriers and diluents may befound in “Remington's Pharmaceutical Sciences” by E. W. Martin and theseinclude water, saline, dextrose solution, serum solution, Ringer'ssolution, polyethylene glycol (e.g PEG400), a surfactant (e.gCremophor), a cyclopolysaccharide (e.g hydroxypropyl-3-cyclodextrin orsulfobutyl ether β-cyclodextrins), a polymer, a liposome, a micelle, ananosphere, etc.

In the third aspect of the present invention, there is provided a kitcomprising a combination according to the first aspect of the presentinvention and, optionally, instructions for treating a patient.Typically, a kit can comprise a compound of formula I orpharmaceutically acceptable salt thereof, a glucocorticoid, and aproteasome inhibitor together with instructions for treating a patient.Each active agent can be provided in a suitable container. The kit mayfurther comprise a delivery system, e.g. for the compound of formula Ior pharmaceutically acceptable salt thereof, the glucocorticoid or theproteasome inhibitor or any combination thereof.

The instructions may advise administering the glucocorticoid, thecompound of formula I or a pharmaceutically acceptable salt thereof and,if present, the proteasome inhibitor of the combination concurrently,sequentially or separately according to variables such as the specificcondition being treated, the state of that condition, the activity ofthe specific compounds employed; the specific combination employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compounds employed; the duration of the treatment; drugs usedin combination or contemporaneously with the specific compoundsemployed; and like factors well known in the medical arts.

Preferred kits according to the third aspect of the present inventioninclude those comprising the preferred combinations of the presentinvention as described and exemplified above.

In the fourth aspect of the present invention, there is provided thecombination, composition or kit according to the first, second or thirdaspect of the present invention for use in the treatment of cancer.

In the fifth aspect of the present invention, there is provided a methodof treating cancer in a patient in need thereof comprising administeringto said patient the combination, composition or kit according to thefirst, second or third aspect of the present invention.

It has been found that the combinations, compositions and kits of thepresent invention are highly active both in vitro and in vivo against awide variety of tumour cell types. The anti-tumour activity shown bythese double and triple combinations of the present invention, and bythe combinations in the compositions and kits of the present inventionis, in many cases, more than merely additive, showing combinationindexes CI of significantly less than 1, indicating synergy for thesecombinations. This surprising finding is a further support for theparticular effectiveness of the combinations, compositions and kits ofthe present invention in the treatment of cancer.

Examples of cancers which are treatable by the combinations,compositions and kits of the present invention include hematologiccancers such as multiple myeloma, lymphoma and leukemia, breast cancer,lung cancer, colorectal cancer, prostate cancer, testicular cancer,pancreatic cancer, liver cancer, stomach cancer, biliary tract cancer,esophageal cancer, gastrointestinal stromal tumor, cervical cancer,ovarian cancer, uterine cancer, renal cancer, melanoma, basal cellcarcinoma, squamous cell carcinoma, bladder cancer, sarcoma,mesothelioma, thymoma, myelodysplastic syndrome, glioblastoma andmyeloproliferative disease. In particular, the combinations,compositions and kits of the present invention are effective againsthematologic cancer such as multiple myeloma, lymphoma and leukemia, andbreast cancer. In one embodiment of the combination, composition or kitfor use in the treatment of a cancer according to the fourth aspect ofthe present invention or the method of treatment according to the fifthaspect of the present invention, the cancer is selected from ahematologic cancer and breast cancer.

Where the combination, composition or kit of the present invention isfor use in the treatment of a hematologic cancer, this may preferably beselected from multiple myeloma (e.g. active myeloma, plasmacytoma, lightchain myeloma or non-secretory myeloma), lymphoma (e.g. Hodgkin lymphomaor non-Hodgkin lymphoma) and leukemia [acute lymphoblastic leukemia(ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML,including myeloblastic leukemia, acute promyelocytic leukemia, acutemyelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemiaand acute megakaryotic leukemia, with all forms being treatable in allphases including relapsed and refractory phases), chronic myeloidleukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocyticleukemia (T-PLL), large granular lymphocytic leukemia or T-cell acutelymphoblastic leukemia].

Where the combination, composition or kit of the present invention isfor use in the treatment of breast cancer, the breast cancer maytypically be selected from claudin-low tumors, basal-like tumors, humanepidermal growth factor receptor 2 (HER2) positive tumors, luminal Atumors and luminal B tumors, and it is preferably a triple-negativebreast cancer.

In one preferred embodiment of the combination, composition or kit foruse in the treatment of cancer according to the present invention andthe method of treatment of cancer according to the present invention,the glucocorticoid, the compound of formula I or a pharmaceuticallyacceptable salt thereof and, if present, the proteasome inhibitor areadministered concurrently, sequentially or separately. More preferably,the glucocorticoid, the compound of formula I or a pharmaceuticallyacceptable salt thereof and, if present, the proteasome inhibitor areadministered concurrently.

In the combination, composition or kit for use in the treatment ofcancer and the method of treatment of cancer in accordance with thepresent invention, the compound of formula I or a pharmaceuticallyacceptable salt thereof is typically administered to the patient in needthereof at a dosage range of 10 to 100 mg/kg body weight patient, andpreferably at a dosage range of 40 to 80 mg/kg body weight patient.Typically, the glucocorticoid is administered at a dosage range of from0.1 to 1 mg/kg body weight patient and preferably at a dosage range offrom 0.3 to 0.5 mg/kg body weight patient. Where a proteasome inhibitoris also administered to the patient together with the compound offormula I or a salt thereof and the glucocorticoid, it is typicallyadministered at a dosage range of 0.01 to 0.3 mg/kg body weight patient.Preferably, the proteasome inhibitor is administered to the patient at adosage range of 0.05 to 0.15 mg/kg body weight patient.

The therapeutically effective amount of a combination, composition orkit according to the present invention is an amount of the combination,composition or kit which confers a therapeutic effect in accordance withthe fourth and fifth aspects of the present invention on the treatedsubject, at a reasonable benefit/risk ratio applicable to any medicaltreatment. The therapeutic effect may be objective (i.e. measurable bysome test or marker) or subjective (i.e. subject gives an indication ofor feels an effect). An effective amount of the combination, compositionor kit according to the present invention is believed to be one whereinthe compound of formula I or a salt thereof is included in thecombination at a dosage range of from 10 to 100 mg/kg body weightpatient (e.g. 40 to 80 mg/kg body weight such as 40, 50, 60, 70 or 80mg/kg body weight), the glucocorticoid is included at a dosage range offrom 0.03 to 1 mg/kg body weight patient (e.g. 0.3 to 0.5 mg/kg bodyweight patient, such as 0.3, 0.4 or 0.5 mg/kg body weight patient) andthe proteasome inhibitor if present is included at a dosage range offrom 0.01 to 0.3 mg/kg body weight patient (e.g. 0.05 to 0.15 mg/kg suchas 0.05, 0.1 or 0.15 mg/kg body weight).

Effective doses will vary depending on route of administration, as wellas the possibility of co-usage with other active agents. It will beunderstood, however, that the total daily usage of the combinations,compositions and kits of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or contemporaneously with the specific compound employed;and like factors well known in the medical arts. The present inventionis also directed to the use of a combination, composition or kitaccording to the first, second or third aspect of the present inventionin the manufacture of a medicament for the treatment of cancer, e.g. forthe treatment of a hematologic cancer or breast cancer.

Suitable examples of the administration form of the combination,composition or kit of the present invention include without limitationoral, topical, parenteral, sublingual, rectal, vaginal, ocular, andintranasal. Parenteral administration includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques. Preferably, the combinations, compositions and kits areadministered parenterally. Combinations, compositions and kits of theinvention can be formulated so as to allow a combination or compositionof the present invention to be bioavailable upon administration of thecombination, composition or kit to an animal, preferably human.Compositions can take the form of one or more dosage units, where forexample, a tablet can be a single dosage unit, and a container of acombination or composition of the present invention in aerosol form canhold a plurality of dosage units.

Preferably the combinations of the present invention are provided in theform of kits. Typically, a kit includes a glucocorticoid, a compound offormula I or a pharmaceutically acceptable salt thereof and, optionally,a proteasome inhibitor. In certain embodiments, a kit can include one ormore delivery systems, e.g. the glucocorticoid, the compound of formulaI or a pharmaceutically acceptable salt thereof and, optionally, aproteasome inhibitor, or any combination thereof, and directions for theuse of the kit (e.g. instructions for treating a subject). Thesedirections/instructions may advise administering the glucocorticoid, thecompound of formula I or a pharmaceutically acceptable salt thereof and,if present, the proteasome inhibitor of the combination concurrently,sequentially or separately according to variables such as the specificcondition being treated, the state of that condition, the activity ofthe specific compounds employed; the specific combination employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compounds employed; the duration of the treatment; drugs usedin combination or contemporaneously with the specific compoundsemployed; and like factors well known in the medical arts.

The pharmaceutically acceptable diluent or carrier can be particulate,so that the compositions are, for example, in tablet or powder form. Thecarrier(s) can be liquid, with the combinations, compositions or kitsbeing, for example, an oral syrup or injectable liquid. In addition, thecarrier(s) can be gaseous, so as to provide an aerosol compositionuseful in, for example, inhalatory administration. Such pharmaceuticalcarriers can be liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. The carriers can besaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating and coloring agents can be used. In oneembodiment, when administered to an animal, the combination, compositionor kit of the present invention and the pharmaceutically acceptablecarriers are sterile. Water is a preferred carrier when the combinationor composition of the present invention is administered intravenously.Saline solutions and aqueous dextrose and glycerol solutions can also beemployed as liquid carriers, particularly for injectable solutions.Suitable pharmaceutical carriers also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The present compositions, if desired, can also contain minoramounts of wetting or emulsifying agents, or pH buffering agents.

When intended for oral administration, the combination or compositionmay be in solid or liquid form, where semi-solid, semi-liquid,suspension and gel forms are included within the forms considered hereinas either solid or liquid.

As a solid composition for oral administration, the combination,composition or kit can be formulated into a powder, granule, compressedtablet, pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition typically contains one or more inert diluents, either as asingle tablet comprising all active agents or as a number of separatesolid compositions, each comprising a single active agent of thecombination of the present invention (in the case of the kit). Inaddition, one or more of the following can be present: binders such ascarboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, orgelatin; excipients such as starch, lactose or dextrins, disintegratingagents such as alginic acid, sodium alginate, corn starch and the like;lubricants such as magnesium stearate; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the combination or composition is in the form of a capsule (e. g. agelatin capsule), it can contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol, cyclodextrin or afatty oil.

The combination, composition or kit can be in the form of a liquid, e.g. an elixir, syrup, solution, emulsion or suspension. The liquid can beuseful for oral administration or for delivery by injection. Whenintended for oral administration, a combination, composition or kit cancomprise one or more of a sweetening agent, preservatives, dye/colorantand flavor enhancer. In a combination or composition for administrationby injection, one or more of a surfactant, preservative, wetting agent,dispersing agent, suspending agent, buffer, stabilizer and isotonicagent can also be included. In the kit of the present invention, theliquid components comprising one or more of the active agents of thecomposition may either be combined prior to administration andadministered concurrently or each active agent may be administeredsequentially or separately.

The preferred route of administration is parenteral administrationincluding, but not limited to, intradermal, intramuscular,intraperitoneal, intravenous, subcutaneous, intranasal, epidural,intranasal, intracerebral, intraventricular, intrathecal, intravaginalor transdermal. The preferred mode of administration is left to thediscretion of the practitioner, and will depend in part upon the site ofthe medical condition (such as the site of cancer). In a more preferredembodiment, the present combinations, compositions and kits of thepresent invention are administered intravenously.

The liquid combinations, compositions and kits of the invention, whetherthey are solutions, suspensions or other like form, can also include oneor more of the following: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides, polyethylene glycols, glycerin, or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben; andagents for the adjustment of tonicity such as sodium chloride ordextrose. A parenteral combination or composition can be enclosed in anampoule, a disposable syringe or a multiple-dose vial made of glass,plastic or other material. Physiological saline is a preferred adjuvant.

For administration (e.g. intravenous) the combination or composition maytypically comprise the compound of formula I or a salt thereof at adosage range of from 10 to 100 mg/kg body weight patient, theglucocorticoid at a dosage range of from 0.1 to 1 mg/kg body weightpatient and the proteasome inhibitor at a dosage range of from 0.01 to0.3 mg/kg body weight patient. More preferably, the combination orcomposition may typically comprise the compound of formula I or a saltthereof at a dosage range of from 40 to 80 mg/kg body weight patient,the glucocorticoid at a dosage range of from 0.3 to 0.5 mg/kg bodyweight patient and the proteasome inhibitor at a dosage range of from0.05 to 0.15 mg/kg body weight patient.

The combinations of the inventions may be formulated such that theglucocorticoid, the compound of formula I or a pharmaceuticallyacceptable salt thereof and, if present, the proteasome inhibitor areadapted for administration concurrently, sequentially or separately.Preferably, they are administered concurrently.

The combination, composition or kit of the present invention can beadministered by any convenient route, for example by infusion or bolusinjection, by absorption through epithelial or mucocutaneous linings.

In specific embodiments, it can be desirable to administer one or morecombinations, compositions or kits of the present invention orcombinations, compositions or kits locally to the area in need oftreatment. In one embodiment, administration can be by direct injectionat the site (or former site) of a cancer, tumor or neoplastic orpre-neoplastic tissue.

Pulmonary administration can also be employed, e. g. by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the combination, composition or kit of the presentinvention or compositions can be formulated as a suppository, withtraditional binders and carriers such as triglycerides.

The present combination, composition or kit can take the form ofsolutions, suspensions, emulsion, tablets, pills, pellets, capsules,capsules containing liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. Other examples of suitable pharmaceuticalcarriers are described in “Remington's Pharmaceutical Sciences” by E. W.Martin.

The pharmaceutical combinations, compositions and kits can be preparedusing methodology well known in the pharmaceutical art. For example, acomposition intended to be administered by injection can be prepared bycombining the components of a kit of the present invention with water soas to form a solution. A surfactant can be added to facilitate theformation of a homogeneous solution or suspension.

The combinations, compositions and kits of the present invention areparticularly effective in the treatment of cancer. The combinations,compositions and kits of the present invention have been shown to haveexcellent activity against a wide variety of tumor cell types both invitro and in vivo, making them particularly interesting for developmentfor use in the treatment of cancer, e.g. hematologic cancer and breastcancer.

EXAMPLES

In the following examples, the compound having the following formula Iis referred to as EDO-S101 (or EDO in the Figures):

This can be prepared as described in Example 5 of WO-A-2010/085377.

Example 1 EDO-S101 Combinations In Vitro—Multiple Myeloma MMIS Cell Line

EDO-S101 was combined in vitro with dexamethasone and bortezomib in themultiple myeloma MMIS cell line (obtained from LGC Standards S.a.r.I.,6, rue Alfred Kastler, BP 83076, F-67123 Molsheim Cedex, France).Activity was measured by the MTT assay that is based on the metabolicbromide reduction from3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole (MTT), which isproduced by the mitochondrial enzyme succinate-dehydrogenase, turned toa blue-colored compound named formazan. The mitochondrial functionalityof the treated cells is then determined. This method has beenextensively used to measure cell proliferation and survival capacities.The remaining living cells are proportional to the amount of formazanproduced.

In brief the methodology was as follows:

-   -   30,000 MM1S cells per well were plated into the 96-well        microtiter plates.    -   EDO-S101 and PI dilutions were prepared in DMSO and        dexamethasone in ethanol and added into the wells to the final        concentrations indicated in the experiment.    -   Plates were incubated for 24-48-72 hours in the incubator at        37° C. in a humidified atmosphere in the presence of 5% CO₂/95%        air.    -   After the incubation 10 μL of MTT solution were added in each        well and incubated for 2 hours to allow formazan crystal        formation.    -   100 μl of a mix solution with SDS plus HCl (10 μL of HCl for        each 12 mL of SDS) was added to dissolve the formazan crystals.    -   Absorbance was read at 570 nm OD and use a reference wavelength        of 650 nm.    -   Cell viability (percentage) was obtained as follows: %        Viability=OD treated cells×100/OD control cells.    -   Each dose was tested in quadruplicate and each experiment was        performed at least twice.

The concentrations for the different drugs were ratio constant for allthe experiments. EDO-S101 at 500 nM, 1 μM, 2.5 μM; dexamethasone at 2.5nM; 5 nM; 10 nM; and bortezomib at 0.75 nM, 1.5 nM, 3 nM.

The results are as shown in Table 1 below and FIG. 1.

TABLE 1 48 H CI For experimental values Dexa 48 h EDO 48 h (nM) (nM) FaCI 2.5 500 0.43453 0.851 5 1000 0.56838 0.761 10 2000 0.683802 0.765 CIFor experimental values Bortz 48 h EDO 48 h (nM) (nM) Fa CI 0.75 5000.247333 1.087 1.5 1000 0.452958 1.230 3 2000 0.918526 0.627 CI Forexperimental values DOBLE Dexa 48 h Bortz 48 h (nM) (nM) Fa CI 2.5 0.750.413191 1.105 5 1.5 0.620757 0.879 10 3 0.935984 0.494 CI Forexperimental values Dexa 48 h Bortz 48 h EDO 48 h (nM) (nM) (nM) Fa CI2.5 0.75 150 0.455868 0.958 5 1.5 300 0.673133 0.789 10 3 600 0.9621730.404

The potency of the combination was quantitated with the Calcusynsoftware (blosoft, Ferguson, Mo., USA), which is based on the Chou Talaymethod (Chou et al., Adv. Enzyme Regul., 22, 27-55 (1984)), thatcalculates a combination index (CI) with the following interpretation:

-   -   CI 1>1: antagonist effect, CI=1: additive effect and CI<1        synergistic effect

It can be seen from the FIG. 1 and from above that EDO-S101 showssynergy with both dexamethasone and also shows synergy in a triplecombination with dexamethasone and bortezomib.

In a further experiment, the same constant dose of these drugs wasincubated for 72 hours instead of 48 hours. The results are as shown inTable 2 below and FIG. 2

TABLE 2 72 H CI For experimental values DEXA EDO (nM) (nM) Fa CI 2.5 5000.576413 0.682 5 1000 0.69365 0.836 10 2000 0.828332 0.829 CI Forexperimental values BORTZ EDO (nM) (nM) Fa CI 0.75 500 0.310537 1.3361.5 1000 0.780181 1.166 3 2000 0.999302 0.489 CI For experimental valuesDEXA BORTZ (nM) (nM) Fa CI 2.5 0.75 0.411026 1.441 5 1.5 0.865318 0.87610 3 1 0.017 CI For experimental values DEXA BORTZ EDO (nM) (nM) (nM) FaCI 2.5 0.75 500 0.607118 1.115 5 1.5 1000 0.923936 0.845 10 3 2000 10.017

Again, it can be seen from FIG. 2 and the above results in Table 2 thatEDO-S101 shows synergy with dexamethasone and also shows synergy in atriple combination with dexamethasone and bortezomib.

Example 2 EDO-S101 Combinations In Vivo Against a Xenograft ofSubcutaneous Plasmacytoma

CB17-SCID mice (obtained from The Jackson Laboratory, Bar Harbor, Me.)were subcutaneously inoculated into the right flank with 3×10⁶ multiplemyeloma MM1S cells (obtained from LGC Standards S.a.r.I., 6, rue AlfredKastler, BP 83076, F-67123 Molsheim Cedex, France) in 100 μL RPMI 1640medium and 100 μL of Matrigel (BD Biosciences). When tumours becamepalpable, mice were randomized to 8 groups of treatment with 5 mice ineach one.

The groups were:

-   -   Control (group treated with vehicle alone)    -   Bortezomib 1 mg/kg twice weekly intraperitoneal for three weeks    -   Dexamethasone 0.5 mg twice weekly intravenously for three weeks    -   EDO-S101 intravenously at doses of 30 mg/kg once weekly for 3        doses,    -   Bortezomib plus dexamethasone    -   Bortezomib plus EDO-S101    -   EDO-S101 plus dexamethasone    -   Triple combination of EDO-S101 plus Bortezomib and dexamethasone

Caliper measurements of the tumor diameters were performed every day,and the tumor volume was estimated as the volume of an ellipse using thefollowing formula: V=4/3π×(a/2)×(b/2)2, where “a” and “b” correspond tothe longest and shortest diameter, respectively.

The tumour growth results are as shown in FIG. 3 in a plot of tumourgrowth (mm³) against the number of days of study. It can be seen thatthe combination of EDO-S101 and dexamethasone results in tumour volumeslower than that seen with either agent alone while the triplecombination of EDO-S101, bortezomib and dexamethasone shows verysignificantly lower tumour volumes by the end of the study than any ofthe active agents individually.

In conclusion, it can be seen that the compound of formula I (EDO-S101)show excellent activity in combination with glucocorticoid inhibitorssuch as dexamethasone in acting both in vitro and in vivo againstmultiple myelomas. Furthermore, it can be seen that the activity ofthese combinations is surprisingly synergistic. Yet further, it is seenthat triple combinations comprising the compound of formula I, aglucocorticoid and a proteasome inhibitor such as bortezomib showedparticularly strong synergy. It is to be expected that thesecombinations will be active against a wide range of hematologic cancers,not just myeloma but other hematologic conditions such as lymphoma andleukemia. We also believe that these combinations are likely to beactive against other cancers such as breast cancer.

As a result, it is to be expected that combinations of the compound offormula I of the present invention with a glucocorticoid, optionallycomprising a proteasome inhibitor, will be of use in the treatment ofcancer, particularly hematologic cancers and breast cancer.

1. A combination comprising a glucocorticoid and a compound of formula Ior a pharmaceutically acceptable salt thereof:


2. The combination according to claim 1, wherein the pharmaceuticallyacceptable salt of the compound of formula I is a hydrochloride,hydrobromide, hydroiodide, sulfate, bisulfate, sulfamate, nitrate,phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate,glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate,tosylate, salicylate, lactate, naphthalenesulfonate or acetate salt. 3.The combination according to claim 1, wherein the glucocorticoid isselected from the group consisting of dexamethasone, fluocinoloneacetonide and prednisone.
 4. The combination according to claim 1,wherein the glucocorticoid is dexamethasone.
 5. The combinationaccording to claim 1, further comprising a proteasome inhibitor.
 6. Thecombination according to claim 1, further comprising a proteasomeinhibitor selected from the group consisting of bortezomib, carfilzomib,marizomib, delanzomib (CEP-18770), oprozomib (ONX 0912), ixazomib(MLN-9708), LU-102, and a pharmaceutically acceptable salt thereof. 7.The combination according to claim 1, further comprising a proteasomeinhibitor selected from bortezomib, carfilzomib and LU-102.
 8. Thecombination according to claim 1, further comprising one or moreadditional pharmaceutically active agents.
 9. The combination accordingto claim 1, wherein the compound of formula I or pharmaceuticallyacceptable salt thereof, the glucocorticoid and, an optional proteasomeinhibitor are adapted for administration concurrently, sequentially orseparately.
 10. The combination according to claim 1, wherein thecompound of formula I or pharmaceutically acceptable salt thereof, theglucocorticoid and, an optional proteasome inhibitor are adapted foradministration concurrently.
 11. The combination according to claim 1,wherein the molar ratio of the glucocorticoid to the compound of formulaI or pharmaceutically acceptable salt thereof in said combination isfrom 1:500 to 500:1.
 12. The combination according to claim 1, whereinthe molar ratio of the glucocorticoid to the compound of formula I orpharmaceutically acceptable salt thereof in said combination is from1:500 to 1:100.
 13. The combination according to claim 1, wherein themolar ratio of the glucocorticoid to the compound of formula I orpharmaceutically acceptable salt thereof in said combination is from1:300 to 1:100.
 14. The combination according to claim 1, wherein themolar ratio of the glucocorticoid to the compound of formula I orpharmaceutically acceptable salt thereof in said combination is from1:250 to 1:150.
 15. The combination according to claim 1, comprising thecompound of formula I or the acetate salt thereof, and dexamethasone,wherein the molar ratio of dexamethasone to the compound of formula I orthe acetate salt thereof in said combination is from 1:250 to 1:150. 16.The combination according to claim 1, wherein the glucocorticoid and thecompound of formula I or pharmaceutically acceptable salt thereof form asynergistic combination.
 17. The combination according to claim 1,further comprising a proteasome inhibitor, wherein the molar ratio ofthe proteasome inhibitor to the compound of formula I orpharmaceutically acceptable salt thereof to the glucocorticoid in saidcombination is from 1:1000:10 to 1000:1:20.
 18. The combinationaccording to claim 1, further comprising a proteasome inhibitor, whereinthe molar ratio of the proteasome inhibitor to the compound of formula Ior pharmaceutically acceptable salt thereof to the glucocorticoid usedin said combination is from 1:1000:10 to 1:100:2.
 19. The combinationaccording to claim 1, further comprising a proteasome inhibitor, whereinthe molar ratio of the proteasome inhibitor to the compound of formula Ior pharmaceutically acceptable salt thereof to the glucocorticoid usedin said combination is from 1:700:4 to 1:400:3.
 20. The combinationaccording to claim 1, further comprising a proteasome inhibitor selectedfrom bortezomib and carfilzomib, the compound of formula I or theacetate salt thereof and dexamethasone, wherein the molar ratio of theproteasome inhibitor selected from bortezomib and carfilzomib to thecompound of formula I or the acetate salt thereof to dexamethasone insaid combination is from 1:700:4 to 1:400:3.
 21. The combinationaccording to claim 1, further comprising a proteasome inhibitor selectedfrom LU-102, the compound of formula I or the acetate salt thereof anddexamethasone, wherein the molar ratio of LU-102 to the compound offormula I or the acetate salt thereof to dexamethasone in saidcombination is from 1:3:4 to 1:0.5:3.
 22. The combination according toclaim 1, comprising the compound of formula I or pharmaceuticallyacceptable salt thereof, the glucocorticoid and a proteasome inhibitor,wherein the compound of formula I or the pharmaceutically acceptablesalt thereof, the glucocorticoid and the proteasome inhibitor form asynergistic combination.
 23. A pharmaceutical composition comprising apharmaceutically acceptable diluent or carrier and a combinationaccording to claim
 1. 24. A kit comprising a combination according toclaim 1, and optionally, instructions for treating a patient. 25-40.(canceled)
 41. A method of treating cancer in a patient in need thereofcomprising administering to said patient a combination according toclaim
 1. 42. The method according to claim 41, wherein said cancer isselected from a hematologic cancer and breast cancer.
 43. The methodaccording to claim 41, wherein said cancer is hematologic cancerselected from multiple myeloma, lymphoma and leukemia.
 44. The methodaccording to claim 41, wherein said cancer is multiple myeloma selectedfrom active myeloma, plasmacytoma, light chain myeloma and non-secretorymyeloma.
 45. The method according to claim 41, wherein said cancer islymphoma selected from Hodgkin lymphoma and non-Hodgkin lymphoma. 46.The method according to claim 41, wherein said cancer is leukemiaselected from acute lymphoblastic leukemia (ALL), chronic lymphocyticleukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia(CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia(T-PLL), large granular lymphocytic leukemia and T-cell acutelymphoblastic leukemia.
 47. The method according to claim 41, whereinsaid cancer is breast cancer selected from claudin-low tumors,basal-like tumors, human epidermal growth factor receptor 2 (HER2)positive tumors, luminal A tumors and luminal B tumors.
 48. The methodaccording to claim 41, wherein said cancer is a triple negative breastcancer.
 49. The method according to claim 41, wherein in said method theglucocorticoid, the compound of formula I or pharmaceutically acceptablesalt thereof and, an optional proteasome inhibitor are administeredconcurrently, sequentially or separately.
 50. The method according toclaim 41, wherein in said method the glucocorticoid, the compound offormula I or pharmaceutically acceptable salt thereof and, an optionalproteasome inhibitor are administered concurrently.
 51. The methodaccording to claim 41, wherein the compound of formula I orpharmaceutically acceptable salt thereof is administered to the patientin need thereof at a dosage range of 10 to 100 mg/kg body weightpatient.
 52. The method according to claim 41, wherein the compound offormula I or pharmaceutically acceptable salt thereof is administered tothe patient in need thereof at a dosage range of 40 to 80 mg/kg bodyweight patient.
 53. The method according to claim 41, wherein theglucocorticoid is administered at a dosage range of from 0.1 to 1.0mg/kg body weight patient.
 54. The method according to claim 41, whereinthe glucocorticoid is administered at a dosage range of from 0.3 to 0.5mg/kg body weight patient.
 55. The method according to claim 41, whereinthe combination further comprises a proteasome inhibitor, and wherein inthe method, the proteasome inhibitor is administered to the patient at adosage range of 0.01 to 0.3 mg/kg body weight patient.
 56. The methodaccording to claim 41, wherein the combination further comprises aproteasome inhibitor and wherein in the method, the proteasome inhibitoris administered to the patient at a dosage range of 0.05 to 0.15 mg/kgbody weight patient.